This application is a request for a Mentored Patient-Oriented Research Career Developmental Award (K23) to support the training of Dr. Jennifer King in clinical research related to antiretroviral pharmacokinetics. Dr. King is an Assistant Professor in the Department of Pharmacology and Toxicology at the University of Alabama at Birmingham. The proposed training is designed to facilitate her transition into an independent clinical investigator while allowing her to gain the necessary tools to become a leader in pharmacokinetic/dynamic modeling and women's issues surrounding antiretroviral pharmacology. Her training will be supervised by Dr. Edward Acosta, a leading pharmacologist in antiretroviral therapy, Dr. Richard Brundage, an expert in the field of pharmacometrics, Dr. Laura Bachmann, a physician specializing in the care of HIV-infected women and Dr. Jeannette Lee, a biostatistician. The combined resources offered by the University of Alabama at Birmingham's Center for AIDS Research and the Department of Pharmacology and Toxicology are ideal for her training and career development. Dr. King proposes three specific aims in her research proposal. In Specific Aim 1, the pharmacokinetics of total, free and intracellular antiretrovirals in healthy volunteers during two phases of the menstrual cycle will be examined. In Specific Aim 2, ADAPT and NONMEM software will be used to develop a population pharmacokinetic model which may account for unexplained variability in antiretroviral pharmacokinetics due to phase of menstrual cycle and/or sex hormone level. In Specific Aim 3, data from Aims 1 and 2 will be utilized to investigate the pharmacokinetics of total, free and intracellular antiretrovirals in HIV-infected patients during two phases of the menstrual cycle. Sex-differences in antiretroviral pharmacokinetics have been described, especially for protease inhibitors. Mechanisms for these differences have not been elucidated. Understanding the influence of the menstrual cycle on antiretroviral pharmacokinetics is the first logical step toward better characterizing sex-related pharmacokinetic and pharmacodynamic differences between men and women, which is our long-term goal. Results from this study will improve our knowledge base regarding sex differences in antiretroviral clinical pharmacology and potentially lead to a re-examination of conducting early phase clinical trials, drug-drug interaction studies, and pharmacokinetic studies evaluating sex differences. [unreadable] [unreadable] [unreadable]